ORGANIC LETTERS
Regioselective Synthesis of the Bridged Tricyclic Core of Garcinia Natural Products via Intramolecular Aryl Acrylate Cycloadditions
2002 Vol. 4, No. 6 909-912
Eric J. Tisdale, Chinmay Chowdhury, Binh G. Vong, Hongmei Li, and Emmanuel A. Theodorakis* Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093-0358
[email protected] Received December 20, 2001
ABSTRACT
Two different routes to the tricyclic core of Garcinia-derived natural products are described. The first approach is based on a tandem Claisen/ Diels−Alder rearrangement and delivers the desired lactone 14. The second approach, employing a Wessely oxidation/Diels−Alder protocol, leads to the same caged heterocycle, albeit with modified constitution.
The Guttiferae family of tropical plants, specifically those of the genus Garcinia, has yielded an abundance of biologically active and structurally intriguing natural products.1 Among them, morellin (1)2 (Figure 1), produced by Garcinia morella, is the first known example of a xanthonoid natural product containing the 4-oxatricyclo[4.3.1.03,7]decan-2-one scaffold. Since the initial disclosure of morellin’s intriguing structure, many other natural products sharing the same caged skeleton have been reported, including morellic acid (2),3 (1) For selected general references on this topic, see: Ollis, W. D.; Redman, B. T.; Sutherland, I. O.; Jewers, K. J. Chem. Soc., Chem. Commun. 1969, 879-880. Kumar, P.; Baslas, R. K. Herba Hungarica 1980, 19, 8191. Thoison, O.; Fahy, J.; Dumontet, V.; Chiaroni, A.; Riche, C.; Tri, M. V.; Sevenet, T. J. Nat. Prod. 2000, 63, 441-446. (2) Rao, B. S. J. Chem. Soc. C 1937, 853-857. Kartha, G.; Ramachandran, G. N.; Bhat, H. B.; Nair, P. M.; Raghavan, V. K. V.; Venkataraman, K. Tetrahedron Lett. 1963, 4, 459-472. (3) Karanjgaongar, C. G.; Nair, P. M.; Venkataraman, K. Tetrahedron Lett. 1966, 7, 687-691. (4) Rukachaisirikul, V.; Kaewnok, W.; Koysomboon, S.; Phongpaichit, S.; Taylor, W. C. Tetrahedron 2000, 56, 8539-8543. (5) Leong, Y.-W.; Harrison, L. J.; Bennett, G. J.; Tan, H. T.-W.; J. Chem. Res., Synop. 1996, 392-393. 10.1021/ol017278w CCC: $22.00 Published on Web 02/16/2002
© 2002 American Chemical Society
scortechiones A and B4 (3, 4), forbesione5 (5), and gaudichaudione H6 (6) (Figure 1). In addition to their striking chemical architecture, most of these compounds exhibit interesting antibacterial activity and cytotoxicity. It has been postulated that such bioactivity results from the 4-oxatricyclo[4.3.1.03,7]decan-2-one moiety as planar xanthones alone do not show a marked biological profile.6 Undoubtedly, the most exceptional example of structure and bioactivity in a Garcinia natural product is that of lateriflorone (7)7 in which the familiar tricyclic scaffold is attached to an unprecedented spiroxalactone core. From the biosynthetic standpoint, these natural products are presumed to derive from a common benzophenone intermediate of a mixed shikimate-acetate pathway that has (6) Cao, S.-G.; Sng, V. H. L.; Wu, X.-H.; Sim, K.-Y.; Tan, B. H. K.; Pereira, J. T.; Goh, S. H. Tetrahedron 1998, 54, 10915-10924. For related gaudichaudiones, see: Cao, S.-G.; Wu, X.-H.; Sim, K.-Y.; Tan, B. K. H.; Pereira, J. T.; Wong, W. H.; Hew, N. F.; Goh, S. H. Tetrahedron Lett. 1998, 39, 3353-3356. Wu, X.-H.; Tan, B. K. H.; Cao, S.-G.; Sim, K.-Y.; Goh, S. H. Nat. Prod. Lett. 2000, 14, 453-458. (7) Kosela, S.; Cao, S.-G.; Wu, X.-H.; Vittal, J. J.; Sukri, T.; Masdianto; Goh, S.-H.; Sim, K.-Y. Tetrahedron Lett. 1999, 40, 157-160.
Li during their pursuit of the total synthesis of forbesione (5).10 Inspired by the unusual tricyclo[4.3.1.03,7]decan-2-one scaffold and the biosynthetic issues mentioned above, we sought to design a general approach to these caged natural products (Figure 3). The strategy was envisioned to lead
Figure 1. Selected natural products from Garcinia plants.
undergone plant-specific prenylations, rearrangements, and/ or oxidation reactions.8 In 1971, Quillinan and Scheinmann suggested that the caged scaffold of these molecules arises in Nature from a tandem Claisen/Diels-Alder rearrangement (Figure 2).9 Setting out to prove the feasibility of such a
Figure 3. Retrosynthetic analysis of tricyclic fragment 14.
Figure 2. Proposed biosynthesis of the caged structures 10 and 12 starting from precursor 8 (see ref 9).
postulate, they heated compound 8 and obtained an isomeric mixture of Claisen/Diels-Alder adducts 10 and 12. An initial nonregioselective Claisen rearrangement leads to the formation of intermediates 9 and 11 and, thus, the mixture of 10 and 12. A similar mixture of isomers, produced via a Claisen/ Diels-Alder reaction, was also reported by Nicolaou and 910
exclusively to the desired structure while allowing the flexibility to create analogues of the biologically active portion of the Garcinia-derived caged xanthonoids. With the C1-oxygenated Garcinia natural products in mind (lateriflorone numbering), we selected compound 14 because it mapped onto the variable retrosynthetic target 13 in a desirable manner. From a retrosynthetic standpoint, the gemdimethyl group at the C5 carbon center of 13 was pictured to arise from an organometallic addition to lactone 14 followed by cyclodehydration.11 The tricyclic structure of 14 could be formed via a Diels-Alder cycloaddition of intermediate 15, which in turn could arise from either 16 or 17 after a Wessely oxidation12 or a Claisen rearrangement,13 respectively. Both 16 and 17 could be produced from readily available 2,5-dimethoxybenzaldehyde (18), thereby increas(8) Bennett, G. J.; Lee, H.-H. J. Chem. Soc., Chem. Commun.1988, 619620. (9) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Chem. Commun. 1971, 966-967. (10) Nicolaou, K. C.; Li, J.; Angew. Chem., Int. Ed. 2001, 40, 42644268. (11) Raghavan, S.; Rao, G. S. R. S. Tetrahedron 1994, 50, 2599-2616. Org. Lett., Vol. 4, No. 6, 2002
ing the convergency of both strategies. Herein, we disclose the results of our studies based on these retrosynthetic considerations. The synthesis of the Wessely oxidation/Diels-Alder precursor 16 is shown in Scheme 1. Commercially available
Scheme 1.
Synthesis of Lactone 24a
a Reagents and conditions: (a) 1.3 equiv of mCPBA, CH Cl , 4 2 2 h, 25 °C; (b) 10% NaOH (aq)/MeOH (1:1), 25 °C, 30 min, 97%; (c) 1.2 equiv of 20, 1.3 equiv of DBU, 0.3 mol % of CuCl2, CH3CN, 0 °C, 24 h, 84%; (d) 10% Pd/BaSO4 (3.2%/weight), quinoline (3.2%/weight), H2, EtOH, 0.5 h, 89%; (e) m-xylene, 140 °C; 2 h, 80%; (f) 1.2 equiv of Pb(OAc)4, acrylic acid (excess), CH2Cl2, 25 °C, 10 min; (g) PhH, 80 °C, 2 h, 82% (over two steps).
2,5-dimethoxybenzaldehyde (18) was subjected to BaeyerVilliger oxidation, and the resulting formate ester was hydrolyzed under basic conditions to produce phenol 19 in 97% yield.14 Various propargylating reagents and conditions were used to alkylate alcohol 19, among which carbonate 20 was found to give optimum results when used in (12) Wessely, F.; Sinwell, F. Monatsch. Chem. 1950, 81, 1055. Wessely, F.; Swoboda, J.; Guth, V. Monatsch. Chem. 1964, 95, 649. Bubb, W. A.; Sternhell, S. Tetrahedron Lett. 1970, 11, 4499-4502. For recent synthetic applications of the Wessely oxidation, see: Cox, C.; Danishefsky, S. J. Org. Lett. 2000, 2, 3493-3496. Feldman, K. S.; Lawlor, M. D. J. Am. Chem. Soc. 2000, 122, 7396-7397. (13) Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157. For recent and selected reviews on Claisen rearrangement, see: Nowicki, J. Molecules 2000, 5, 1033-1050. Ito, H.; Taguchi, T. Chem. Soc. ReV. 1999, 28, 43-50. Gajewski, J. J. Acc. Chem. Res. 1997, 30, 219-225. Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452. Wipf, P. In ComprehensiVe Organic Syntheses; Trost, B. M., Fleming, I., Eds.; 1991; Vol. 5, p 827. (14) Wriede, U.; Fernandez, M.; West, K. F.; Harcourt, D.; Moore, H. W. J. Org. Chem. 1987, 52, 4485-4489. Org. Lett., Vol. 4, No. 6, 2002
conjunction with DBU and catalytic copper(II) chloride.15 Under these conditions, ether 21 was produced in consistent yields of 84%. Lindlar-catalyzed partial hydrogenation16 of alkyne 21 gave rise to alkene 22, which upon heating at 140 °C produced Claisen adduct 1617 (71% combined yield), thereby setting the stage for a tandem Wessely oxidation/ Diels-Alder reaction.18 To this end, compound 16 was treated with Pb(OAc)4 in acrylic acid/dichloromethane and the resulting intermediate heated in refluxing benzene to produce tricyclic lactone 24 in 82% combined yield. Crystallographic studies established that 24 was a constitutional isomer of desired structure 14. The connectivity of compound 24 suggested that during the Wessely oxidation the acrylate unit was attached exclusively at the C1 center of 16, instead of the anticipated C3 carbon. This produced diene 23, which subsequently underwent Diels-Alder cycloaddition with the pendant dienophile. The outcome of the Wessely oxidation can be rationalized if we consider that addition at the C1 center is preferred due to the electron-donating effect of the attached methoxy group. Despite the discrepancy in connectivity, lactone 24 assured us an entry point to the tricyclo[4.3.1. 03,7]decan-2-one caged system and suggests that the outcome of the reaction can be altered by decreasing the electron-donating effect of the substituent at the C1 carbon center. Concurrent with the above studies, we examined the feasibility of the tandem Claisen/Diels-Alder rearrangement as an entry point to the 4-oxatricyclo[4.3.1.03,7]decan-2-one scaffold (Scheme 2). To this end, 2,5-dimethoxybenzaldehyde (18) was transformed to alkyne 21, which after a subsequent Claisen rearrangement in refluxing m-xylene, produced benzopyran 25 (61% combined yield). Lactol 26 was acquired from pyran 25 in 22% yield by a fairly consistent three-step protocol involving ozonolysis, a chemoselective Baeyer-Villiger oxidation, and basic hydrolysis. Each step in this string of reactions was carried out on crude material as purification of the intermediates proved to be difficult.19 After purification, compound 26 was subjected to a Wittig olefination protocol to afford phenolic ether 27,20 which upon a straightforward acryloylation produced the Claisen/Diels-Alder precursor 17 in 93% yield. Heating of (15) Godfrey, J. D., Jr.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.; Colandrea, V. J. Tetrahedron Lett. 1994, 35, 6405-6408. (16) Hlubucek, J.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1971, 24, 2355-2363. (17) Rhoads, S. J.; Raulins, N. R. Organic Reactions; Dauben, W. G., Ed.; John Wiley & Sons: New York, 1975; Vol. 22, Chapter 1, pp 1-252. (18) The tandem Wessely oxidation/Diels-Alder reaction has been utilized extensively by Yates and co-workers. For selected examples on this work, see: Bhamare, N. K.; Granger, T.; John, C. R.; Yates, P. Tetrahedron Lett. 1991, 32, 4439-4442. Bhamare, N. K.; Granger, T.; Macas, T. S. Yates, P. J. Chem. Soc., Chem. Commun. 1990, 739-740. Bichan, D. J.; Yates, P. J. Am. Chem. Soc. 1972, 94, 4773-4774. Yates, P.; Kaldas, M. Can J. Chem. 1992, 70, 2491-2501. Yates, P.; Langford, G. E. Can J. Chem. 1981, 59, 344-355. Yates, P.; Auksi, H. J. Chem. Soc., Chem. Commun 1976, 1016-1017. Yates, P.; Auksi, H. Can. J. Chem. 1979, 57, 2853-2863. (19) Both the ozonolysis and the Baeyer-Villiger oxidation reactions tended to be clean. This led to the conclusion that hydrolysis of the intermediate formate ester to lactol 26 was the bottleneck of this protocol. Attempts were made to optimize the reaction sequence, particularly the hydrolysis, but little ground could be gained. (20) Wittig olefination of the pendant aldehyde was also attempted prior to hydrolysis of the formate ester. This change in reaction sequence, however, did not change overall product yields. 911
Scheme 2.
Synthesis of Tricyclic Lactone
14a
a Reagents and conditions: (a) 1.3 equiv of mCPBA, CH Cl , 4 2 2 h, 25 °C; (b) 10% NaOH (aq)/MeOH (1:1), 25 °C, 30 min, 97%; (c) 1.2 equiv of 20, 1.3 equiv of DBU, 0.3 mol % of CuCl2, CH3CN, 0 °C, 24 h, 84%; (d) m-xylene, 140 °C, 2 h, 74%; (e) O3, CH2Cl2, -78 °C, 30 min, then DMS, 30 min; (f) 1.3 equiv of mCPBA, CH2Cl2, 25 °C, 4 h; (g) 10% NaOH (aq)/MeOH (1:1) 30 min, 25 °C, 22% (over three steps); (h) 5.0 equiv of H3CPPh3Br, 4.6 equiv of NaHMDS, THF (inverse addition), 25 °C, 2 h, 65%; (i) 1.1 equiv of acryloyl chloride, 1.2 equiv of TEA, 0.1 equiv of DMAP, CH2Cl2, 0 °C, 1 h, 93%; (j) m-xylene, 140 °C, 45 min, 92%.
17 in boiling m-xylene allowed the tandem Claisen/DielsAlder to take place, thereby producing tricyclic structure 14 in a remarkably efficient process (92% overall yield).
912
Compound 14 was crystalline, and X-ray diffraction studies revealed that it possessed the desired connectivity across the central tetrahydrofuran core. The remarkably efficient and regioselective Claisen/Diels-Alder process owes much of its success to the reversibility of the Claisen rearrangement. While the R,R-dimethylallyl substituent of 17 can migrate and, thus, prenylate either of two adjacent positions, only the desired isomeric intermediate 15 (see Figure 3) adopts a geometry that allows it to be trapped as the Diels-Alder adduct. Consequently, all the available starting material eventually funnels through the desired mechanistic pathway to generate the preferred adduct 14. In conclusion, we have demonstrated, using two different methods, the ability to access the 4-oxatricyclo[4.3.1.03,7]decan-2-one scaffold encountered in many of the Garciniaderived natural products. Both strategies are very efficient and afford the tricyclic structures with excellent regiocontrol. The tandem Claisen/Diels-Alder strategy proceeds in 10 steps (from aldehyde 18) and produces the desired tricyclic scaffold 14. The efficiency of the Claisen/Diels-Alder rearrangement presented here allows access to the desired natural product scaffold in a high-yielding and predictable process. In contrast, the alternative sequence of Wessely oxidation/Diels-Alder reaction gives rise to isomeric structure 24, whose application to the synthesis of the above natural products should await some fine-tuning, especially as related to the electronic effects of the substituents of the aromatic ring. Nonetheless, adduct 24 may be useful for the preparation and biological investigation of nonnatural analogues of the above natural products. Acknowledgment. Financial support from the NIH (CA086079) is gratefully acknowledged. We thank Dr. P. Gantzel (UCSD, X-ray Facility) for the reported crystallographic structures. We also thank the Department of Education for a GAANN Fellowship to B.G.V. Supporting Information Available: 1H and 13C NMR spectra available for compounds 14, 16, 17, 22, 24, 26, and 27. Experimental procedures, spectroscopic, and analytical and X-ray data for compounds 14 and 24. This material is available free of charge via the Internet at http://pubs.acs.org. OL017278W
Org. Lett., Vol. 4, No. 6, 2002
